Identification and Characterization of Epigenetically Labile Genes

描述（由申请人提供）： 单卵双胞胎以及遗传相同的生物体中不一致的表型和复杂疾病的不同发病率长期以来一直被归因于不同的环境暴露。然而，越来越多的证据表明，DNA甲基化和环境暴露引起的组蛋白修饰引起的表观遗传基因失调也在这种疾病易感性差异中发挥作用。因此，这项拨款申请的首要假设是，早期暴露于环境因素影响成人疾病的易感性，通过引起稳定的改变，在关键的DNA控制元件，调节亚稳态表观等位基因-基因的表观基因组是建立在发展过程中的概率，导致可变的基因表达和广泛变化的个人成人表型。尽管表观遗传学在人类慢性疾病病因学中的重要性越来越得到共识，但最容易发生表观遗传失调的基因并不完全确定。此外，无论是最强烈地影响表观基因组的环境因素，也没有环境诱导的表观遗传改变的脆弱性的关键窗口的特点。这些知识的主要缺陷严重限制了我们系统地定义和表征人类疾病病因学中涉及的亚稳态表观等位基因的能力。这项资助申请的总体目标是通过使用可行的黄色Agglomerus（Avy）小鼠模型以及人类样本来识别小鼠和人类基因组中的环境响应性亚稳态表观等位基因，以帮助纠正这些缺陷。具体而言，目的是确定母体饮食补充低水平的增塑剂双酚A（BPA）的Avy小鼠是否通过改变胎儿表观基因组影响后代的成年表型。将采用基因表达和全基因组生物信息学方法来鉴定小鼠和人类中的印迹和非印迹亚稳态表观等位基因。这项研究的结果最终应该允许通过靶向表观基因组而不是基因组来改善对慢性人类疾病如哮喘、糖尿病、癌症、肥胖和神经系统疾病的诊断、治疗和预防。它们还将有助于确定在何种情况下小鼠是评估主要通过改变表观基因组引起其生物学效应的药剂对人类风险的适当毒理学模型。

DESCRIPTION (provided by applicant): Discordant phenotypes and varying incidences of complex diseases in monozygotic twins as well as genetically identical organisms have long been attributed to differential environmental exposures. Accumulating evidence indicates, however, that epigenetic gene dysregulation by DNA methylation and histone modifications from environmental exposures also play a role in this differential susceptibility to disease. Thus, the overarching hypothesis of this grant application is that early exposure to environmental agents influences adult disease susceptibility by causing stable alterations in critical DNA control elements that regulate metastable epialleles - genes whose epigenome is established probabilistically during development, leading to variable gene expressivity and widely varying individual adult phenotypes. Despite a growing consensus on the importance of epigenetics in the etiology of chronic human diseases, the genes most prone to epigenetic dysregulation are incompletely defined. Moreover, neither the environmental agents most strongly affecting the epigenome nor the critical windows of vulnerability to environmentally induced epigenetic alterations have been characterized. These major deficits in knowledge have severely constrained our ability to systematically define and characterize the metastable epialleles mechanistically involved in the etiology of human diseases. The overall objective of this grant application is to help correct these deficiencies by using the viable yellow Agouti (Avy) mouse model, as well as human samples to identify environmentally responsive, metastable epialleles in the mouse and human genomes. Specifically, the intent is to determine if maternal dietary supplementation of Avy mice with low levels of the plasticizer bisphenol A (BPA) affects adult phenotype of the offspring by altering the fetal epigenome. Gene expression and genome-wide bioinformatic approaches to identify imprinted and non-imprinted metastable epialleles in both mice and humans will be employed. The results of this study should ultimately allow for improved diagnosis, treatment, and prevention of chronic human diseases such as asthma, diabetes, cancer, obesity and neurological disorders by targeting the epigenome rather than the genome. They will also be helpful in determining under what circumstances the mouse is an appropriate toxicological model for assessing human risk from agents that elicit their biological effect primarily by altering the epigenome.